Project Summary Health challenges linked to human aging take a tremendous toll on our society. Physical and cognitive decline limit the quality of life for the elderly and their caregivers. Aging is the major risk factor for, and possible cause of cancer, diabetes, and neurodegenerative disease, and thus struggle with debilitating disease is a common health burden for the aging population. Without question, the promotion of healthy aging with extended resistance to decline should be a major objective of current medical research. To investigate healthy aging, simple animals models such as the nematode C. elegans have been used to provide molecular insights into the genes and chemical compound interventions that can modulate conserved aging processes likely to act similarly in humans. The goal of the proposed work is to continue, and expand, efforts of a co-operative scientific group involving three closely interacting laboratories who coordinately test pharmacological interventions for their ability to extend healthy aging and promote longevity in nematodes. A specific emphasis of this integrated super-group is to test promising drugs on a collection of natural variants of the Caenorhabditis genus, which together represent the extensive genetic heterogeneity in the human population. The idea is that treatments that confer positive outcomes across a diverse population will have an increased chance of being efficacious in higher organisms and will be suggested as priority interventions for testing in pre-clinical mouse studies and possibly future human trials. The emphasis of this specific proposal is the screening of test compounds for the capacity to promote a range of indicators of strong health in older age. We will focus on measures with parallels to human aging: locomotory decline, diminished resistance to stress, deterioration of cardiac-like muscle function, disruption of intestinal barrier function, and accumulation of age-related pigments in non-dividing cells. Our findings will be integrated with parallel evaluation of the same compound interventions on longevity, so that we can define treatments that promote the quality and functionality of older age life, rather than those that simply extend life. Overall, we will participate in a unique team project that has the power to define pharmacological interventions that robustly promote strong healthspan across a varied population, with implications for development of therapies that promote healthy human aging.